Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin

Kanner, Joseph; Harel, Stella; Granit, Rina

doi:10.1007/bf02537058

Cited by 249 publications

(123 citation statements)

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“…Prolongation of the lag phase with a longer presence of NO in the reaction mixture suggests that NO interacts with the rabbit 15-lipoxygenases and converts it to an enzyme species which is less susceptible to product activation. A similar kinetic behaviour has been reported for the soybean lipoxygenase during its interaction with NO [7,201. A possible mechanistic reason for this lower susceptibility towards peroxide activation is the formation of a ferrous lipoxygenase-NO complex.…”

Section: Resultssupporting

confidence: 82%

“…It has been reported before that the soybean lipoxygenase is inhibited reversibly by NO [7], but no detailed kinetic analysis of this effect has been performed. Because of the structural and kinetic similarities of plant and animal 15-lipoxygenases it was straightforward to assume that mammalian 15-lipoxygenases are also inhibited by NO.…”

Section: Discussionmentioning

confidence: 99%

“…Since both plant and mammalian lipoxygenases contain ferrous non-heme iron, an interaction with nitric oxide may be predicted. In fact, for the soybean lipoxygenase an inhibition of the enzyme by nitric oxide has been reported [7,201. This inhibition was accompanied by the formation of a ferrous lipoxygenase-NO complex which has been detected by EPR studies [19-211. Recently we have demonstrated that the mammalian 15-lipoxygenases from rabbit reticulocytes are a150 reversibly inhibited when incubated with NO [22].…”

mentioning

confidence: 99%

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A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

Holzhütter

Wiesner

Rathmann

et al. 1997

European Journal of Biochemistry

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Nitric oxide (NO) has been known for a long while to act as an inactivator of the soybean lipoxygenase-1 and cyclooxygenase. More recently, NO was shown to interact also with a mammalian 15-lipoxygenase [Wiesner, R., Rathmann, J., Holzhiitter, H. G., StoRer, R., Mader, K., Nolting, H. & Kiihn, H. (1996) Nitric oxide oxidises ferrous mammalian lipoxygenases to a pre-activated ferric species, FEBS Lett. 389, 229-2321. In this paper we present a detailed kinetic analysis of the interaction of NO with the 15-lipoxygenase from reticulocytes. Time courses of hydroperoxide formation were monitored after an anaerobic incubation of the enzyme with varying concentrations of NO and for varying length of the incubation period. Owing to the presence of O2 during the enzymatic reaction, the inhibitory effect of NO declines in a time-dependent manner since NO is converted into non-reactive NO, This is manifested as a lag phase of the time course. The lag phase becomes more pronounced if the enzyme is incubated over a fixed period (15 s) with increasing concentrations of NO. In contrast, increasing the length of the incubation period at fixed concentrations of NO diminishes the duration of the lag phase. These experimental findings can be accounted for by a kinetic model which assumes (a) fast reversible binding of NO to the inactive ferrous Fe(I1) form of the enzyme and (b) slow irreversible conversion of the Fe(I1)-NO complex into an activated ferric form of the enzyme which is susceptible to peroxide activation. The rate constants for these two different kinetic modes of NO action were estimated by fitting the solutions of the model equations to the experimental time courses. The dissociation constant of the Fe(I1)-NO complex amounts to 2.5 pM. Computer simulations performed on the basis of the model indicate that the response of the lipoxygenase to increasing intracellular NO concentrations depend upon the available peroxide tone: at low peroxide concentration the enzyme is initially trapped in the inactive ferrous form and thus may be activated by NO via the activated ferric species. On the other hand, at high peroxide concentrations, a partial inhibition of the initially active enzyme is expected.Keywords: lipoxygenase; nitric oxide ; kinetics ; mathematical modeling.Nitric oxide (NO) is a fairly stable radical exhibiting a variety of physiogical activities such as smooth muscle relaxation, inhibition of cell proliferation, inhibition of platelet aggregation and down regulation of the expression of adhesion molecules [I-51. In mammalian cells it is produced by an inducible and by a constitutively expressed nitric oxide synthase. The half-life of NO in aerobic solutions amounts to less than 10 s [6]. In vitro studies on the interaction of nitric oxide with metalloproteins indicated that it is capable of reacting with ferrous heme-and non-heme iron-containing proteins [7, 81 and thus may interfere with metabolic redox reactions. Lipoxygenases are non-heme iron-containing enzymes which catalyse the dioxygenation of polyen...

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

Holzhütter

Wiesner

Rathmann

et al. 1997

European Journal of Biochemistry

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“…These data suggest that nitric oxide may reversibly interact with the rabbit 15-1ipoxygenases and convert it to an enzyme species which is less susceptible to peroxide activation. A similar kinetic behaviour has been reported before for the soybean lipoxygenase-1 [6,8]. Furthermore, we found that the length of the lag period did depend on the NO concentration (not shown).…”

Section: Kinetic Studiessupporting

confidence: 90%

Nitric oxide oxidises a ferrous mammalian lipoxygenase to a pre‐activated ferric species

et al. 1996

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Nitric oxide is known as an inhibitor of soybean lipoxygenase-1. Investigating the interaction of a mammalian 15-lipoxygenase with nitric oxide, we found that this enzyme is also inhibited reversibly when incubated with nitric oxide for a short time period (5 s) under anaerobic conditions. This inhibition may be due to the formation of a dissociable lipoxygenase-nitric oxide complex. With longer incubation periods the ferrous lipoxygenase is oxidised to a ferric form. This oxidation renders the enzyme more susceptible to peroxide activation, causing a timedependent shortening of the kinetic lag phase.

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“…28 Additionally, methemoglobin binds ⅐ NO to form a nitrosyl-hemoglobin ( ⅐ NO-Hb) intermediate that loses its ability to oxidize linoleic acid and produce conjugated dienes as well as the ability to co-oxidize substrates such as ␤-carotene. 29 In general, when ⅐ NO complexes with metalloproteins, lipids are protected from further oxidation by metals and oxidant metabolites of ⅐ NO. However, the relative extent of this reaction in oxidizing membranes and lipoproteins is unclear, because the rate of ⅐ NO reaction with oxidationpropagating species such as LOO ⅐ is 10…”

Section: No Can Modulate Lipid Oxidation By Reacting With Cellular Prmentioning

confidence: 99%

Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation

Bloodsworth

O'Donnell

Freeman

2000

ATVB

129

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Abstract-The regulation of nonenzymatic and enzymatic lipid oxidation reactions by nitric oxide ( ⅐ NO) is potent and pervasive and reveals novel non-cGMP-dependent reactivities for this free radical inflammatory and signal transduction mediator. ⅐ NO and its metabolites stimulate and inhibit lipid peroxidation reactions, modulate enzymatically catalyzed lipid oxidation, complex with lipid-reactive metals, and alter proinflammatory gene expression. Through these mechanisms, ⅐ NO can regulate nonenzymatic lipid oxidation and the production of inflammatory and vasoactive eicosanoids by prostaglandin endoperoxide synthase and lipoxygenase. and the metal centers of metalloproteins. The most well-characterized metal-binding action of ⅐ NO is its capacity to bind to the heme iron of sGC and stimulate the production of cGMP. 3 This activates cGMP-dependent kinases and membrane ion channels, decreases intracellular calcium levels, and allows smooth muscle to relax. 4 Thus, ⅐ NO has been identified as an endothelium-derived relaxing factor and as a central modulator of blood pressure. 5 Stimulation of sGC by ⅐ NO also inhibits platelet aggregation and vessel wall adhesion of platelets.

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Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin

Cited by 249 publications

References 43 publications

A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

Nitric oxide oxidises a ferrous mammalian lipoxygenase to a pre‐activated ferric species

Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation

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